Long term N-acetylcysteine administration rescues liver steatosis via endoplasmic reticulum stress with unfolded protein response in mice

Abstract

Background: Fat accumulation in the liver contributes to the development of non-alcoholic fatty liver disease (NAFLD). N-acetylcysteine (NAC) is an antioxidant, acting both directly and indirectly via upregulation of cellular antioxidants. We examined the mechanisms of liver steatosis after 12 months high fat (HF) diet and tested the ability of NAC to rescue liver steatosis. Methods: Seven-week-old C57BL/6 (B6) male mice were administered HF diet for 12 months (HF group). Two other groups received HF diet for 12 months accompanied by NAC for 12 months (HFD + NAC(1-12)) or 6 months (HFD + NAC(1-6)). The control group was fed regular diet for 12 months (CD group). Results: Liver steatosis was more pronounced in the HF group than in the CD group after 12 month feeding. NAC intake for 6 or 12 months decreased liver steatosis in comparison with HF diet (p < 0.05). Furthermore, NAC treatment also reduced cellular apoptosis and caspase-3 expression. In the unfolded protein response (UPR) pathway, the expression of ECHS1, HSP60, and HSP70 was decreased in the HFD group (p < 0.05) and rescued by NAC therapy. With regards to the endoplasmic reticulum (ER) stress, Phospho-PERK (p-PERK) and ATF4 expression was decreased in the HF group, and only the HFD + NAC(1-12), but not HFD + NAC(1-6) group, showed significant improvement. Conclusion: HF diet for 12 months induces significant liver steatosis via altered ER stress and UPR pathway activity, as well as liver apoptosis. NAC treatment rescues the liver steatosis and apoptosis induced by HF diet.

N-Acetylcysteine alleviates high fat diet-induced hepatic steatosis and liver injuryviaregulating the intestinal microecology in mice

“…NAC dose and administration mode in this study were selected referring to a previous study. 27 In line with previous reports, 17,27 we observed that NAC supplementation significantly improved HFD-induced hepatic steatosis and liver injury.…”

“…Oxidative stress is implicated in the pathological process of NAFLD. Numerous antioxidants, such as NAC, exhibited a strong protective role against HFD-induced NAFLD in mice, 17 indicating antioxidation as a therapeutic strategy to improve NAFLD. As an effective free radical scavenger, NAC is a kind of dietary amino acid in nature, which is the precursor of glutathione synthesis in organisms.…”

N-Acetyl Cysteine Targets Hepatic Lipid Accumulation to Curb Oxidative Stress and Inflammation in NAFLD: A Comprehensive Analysis of the Literature

“…Table 2 summarizes preclinical evidence reporting on the ameliorative effects of NAC against oxidative stress and inflammation in rodent models of NAFLD. Although models of high-fat or cholesterol diet were used to induce liver abnormalities [ 41 , 47 , 51 , 52 ], the majority of included studies employed a methionine–choline-deficient (MCD) diet to assess the impact of oxidative stress and inflammation on NAFLD [ 17 , 53 , 54 , 55 , 56 ]. Interestingly, an MCD diet is a classical dietary model of NASH and progressively used to assess therapeutic effects of various pharmacological compounds in protecting against NAFLD [ 57 ].…”

“…Tsai et al, 2020 [52] NAFLD was induced in male C57BL/6 (B6) mice by administering HF diet for 12 months with NAC (10 mM NAC) dissolved in water for 6 or 12 months.…”

Heat Shock Protein 60 Restricts Release of Mitochondrial dsRNA to Suppress Hepatic Inflammation and Ameliorate Non-Alcoholic Fatty Liver Disease in Mice

“…Exogenous HSP60 alleviates hepatic inflammation in an experimental hepatitis mouse model via a downregulated pro-inflammatory profile in T cells [ 34 ]. Recently, Tsai et al discovered that HSP60 expression was decreased in HFD mice and could be rescued by N-acetylcysteine therapy [ 35 ]. Both intra-articular injection of exogenous HSP60 and transgenic HSP60 overexpression (HSP60Tg) demonstrate resistance against experimental joint inflammation compared to the mock control and wild-type (WT) groups [ 36 ].…”